The pathogenesis of HIV in humans involves parenteral or mucosal sites of entry (), the ability to infect lymphoid, myeloid and perhaps other cell types, and the capacity to exist as replicative viral as well as latent proviral forms. Despite an incomplete understanding of HIV immunity, there is strong evidence suggesting that the development of an effective vaccine against HIV is likely to depend on our ability to design a vaccine which stimulates mucosal and systemic HIV-neutralizing antibody and cell-mediated cytotoxic responses. Attenuated live oral Salmonella typhi stimulate mucosal as well as systemic antibody responses and class I restricted cell- mediated immune responses. One approach toward development of an HIV vaccine, then, is to develop attenuated S. typhi as a live vector vaccine for the delivery of HIV antigens. Using the mouse typhoid model and S. typhimurium strain C5 we will test our hypothesis that Salmonella vectors expressing HIV antigens have the capacity to stimulate HIV-specific mucosal and systemic neutralizing antibody and cell-mediated cytotoxic responses. Accordingly our aims are as follows: AIM 1: Construction of attenuated live oral Salmonella-HIV-1IIIB vector hybrids that induce envelope specific immune responses in mice. AIM 2: Construction of Salmonella-HIV-1IIIB vector hybrids that stimulate immunity against the 24 kD HIV gag-encoded protein and against a putative HIV-1 regulatory element, the nef gene product. The results from these first two aims will enable us to design a S. typhi live vector strain that expresses HIV antigens. Hence: AIM 3: Construction and evaluation in mice, of a live oral attenuated S. typhi-HIV candidate HIV vaccine. The attenuated live oral S. typhi-HIV vectors will be tested using standard preclinical toxicity and stability assays. This incremental approach will produce attenuated live oral S. typhi-HIV candidate vector vaccines with potential for Phase 1 clinical volunteer studies.